Transplacental rotavirus IgG interferes with immune response to live oral rotavirus vaccine ORV-116E in Indian infants☆
Introduction
Rotavirus (RV) is the leading cause of severe gastroenteritis (GE) in children <5 years of age and is estimated to cause ∼125 million clinical cases of GE worldwide and ∼275,000–450,000 deaths every year, ∼85% of which occur in low income countries [1], [2]. Two vaccines, Rotarix® and Rotateq®, are currently licensed internationally [3]. The efficacy of these vaccines against severe rotavirus gastroenteritis (SRGE) was 85–98% in developed countries, but only ∼51% efficacy in low income settings of Africa and Asia [3], [4], [5], [6], [7], [8]. Several factors have been hypothesized to explain this failure, including the RV antibodies in breast milk and the high levels of circulating pre-existing maternal RV antibody in the infant that could inhibit replication of these live oral vaccines [3], [9], [10], [11], [12], [13].
In the late 1980's, a RV isolate, now known as strain 116E, was identified in neonates at a hospital in New Delhi. Further characterization of this strain established it to be a natural human-bovine reassortant [14], [15]. Strain 116E was found to have 10 gene segments from a human RV, but a single gene encoding the surface VP4 protein from a bovine strain. VP4 is a hemagglutinin critical for virus attachment and entry and a target for neutralizing antibodies [10]. The bovine origin of this gene was speculated to allow this virus to replicate well in newborns despite the presence of high titers of transplacental RV antibodies [16], [17]. In fact, newborns naturally infected with this strain were asymptomatic and shed virus in their stool, mounted high levels of RV-specific IgA following the infection, and were subsequently found to be protected against SRGE [18], [19]. A candidate vaccine, ORV-116E, was developed from this strain and phase I and II trials in infants in India demonstrated high rates of seroconversion [16], [17], [20]. Unlike other RV vaccines tested in developing countries including India, ORV-116E induced ∼90% seroconversion in Indian infants when administered as three doses of 105 FFU titered vaccine [4], [21], [22].
Although not proven conclusively, some studies indicate a protective role of RV IgA [23], [24]. Nevertheless, RV IgA responses are considered true indicators of seroconversion to the vaccine [23]. In order to establish if transplacental RV IgG antibody affected the immunogenicity of ORV-116E in neonates, we determined the pre-immunization titer of RV IgG (hereafter referred to as maternal IgG) in serum collected from vaccinees in the recently concluded phase Ia/IIb trial in India [21] and compared this to their IgA response to the vaccine. Interestingly, our analyses demonstrated that the IgA responses to ORV-116E were inversely related to the levels of RV IgG prior to immunization. We also observed that ORV-116E administered at a higher titer could overcome the interference from maternal antibody in a dose-dependent manner. These data highlight the critical importance of administering multiple doses of vaccine in order to enhance immune responses and seroconversion.
Section snippets
Clinical trial details
The phase Ia/IIb trial of the ORV-116E, a randomized, double-blinded, placebo-controlled study (Clinical trials registration: NCT00439660 and ISRCTN57452882) to determine the dose-escalation safety and immunogenicity of the vaccine in infants recruited at 6 weeks of age, has been previously described [21]. Briefly, two doses of vaccine containing 104 FFU and 105 FFU of RV 116E were tested. ORV-116E or placebo was administered at 8, 12, and 16 weeks of age. About 90 infants were enrolled for each
Study population and RV immunity
Of the 369 clinically healthy infants enrolled in the phase Ia/IIb trial, 187 received the 104 FFU dose and 182 received the higher dose of 105 FFU [21]. Following the exclusion criteria described in the methods, data from 124 infants in the 104 FFU dose group and 152 infants in the 105 FFU dose group were considered for analyses. Overall, 62 infants (17%) were excluded from the analyses because of high titers of pre-existing IgA and 24 (6.5%) had a non-vaccine RV infection during the study (Table 1
Discussion
Our results demonstrate a clear inverse relationship between the levels of pre-existing RV IgG and the immune response to ORV-116E vaccine, establishing clearly that maternal antibody interfered with an infant's immune response to rotavirus vaccine. Infants who seroconverted to the vaccine had significantly lower median RV IgG titers than those who failed to seroconvert. Additionally, infants with lower RV IgG titers showed the highest level of seroconversion. These observations were true for
Acknowledgments
We thank Duncan Steele and John Clemens for critical reading of the manuscript and valuable comments. This work was supported by the core grant provided by the Department of Biotechnology, Govt. of India to the National Institute of Immunology and the Translational Health Science and Technology Institute.
References (40)
- et al.
Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial
Lancet
(2010) - et al.
Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial
Lancet
(2010) Mechanisms by which maternal antibodies influence infant vaccine responses: review of hypotheses and definition of main determinants
Vaccine
(2003)- et al.
Maternal antibodies to rotavirus: could they interfere with live rotavirus vaccines in developing countries?
Vaccine
(2011) - et al.
Similarity of the VP4 protein of human rotavirus strain 116E to that of the bovine B223 strain
Virology
(1993) - et al.
Safety and immunogenicity of two live attenuated human rotavirus vaccine candidates, 116E and I321, in infants: results of a randomised controlled trial
Vaccine
(2006) - et al.
Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure
J Pediatr
(1977) - et al.
Low titer maternal antibodies can both enhance and suppress B cell responses to a combined live attenuated human rotavirus and VLP-ISCOM vaccine
Vaccine
(2006) - et al.
Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in Native American populations
J Pediatr
(1997) - et al.
Immunogenicity of high-titre AIK-C or Edmonston-Zagreb vaccines in 3.5-month-old infants, and of medium- or high-titre Edmonston-Zagreb vaccine in 6-month-old infants, in Kinshasa, Zaire
Vaccine
(1994)
Safety and immunogenicity of RIX4414 live attenuated human rotavirus vaccine in adults, toddlers and previously uninfected infants
Vaccine
Global and national estimates of deaths under age five attributable to rotavirus infection
Global networks for surveillance of rotavirus gastroenteritis
Wkly Epidemiol Rec
Oral rotavirus vaccines: how well will they work where they are needed most?
J Infect Dis
Effect of human rotavirus vaccine on severe diarrhea in African infants
N Engl J Med
Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis
N Engl J Med
Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine
N Engl J Med
Factors affecting antibody response of newborns to repeated administrations of the rotavirus vaccine RIT 4237
J Pediatr Gastroenterol Nutr
Rotavirus-specific breast milk antibody in two populations and possible correlates of interference with rhesus rotavirus vaccine seroconversion
J Infect Dis
High titers of circulating maternal antibodies suppress effector and memory B-cell responses induced by an attenuated rotavirus priming and rotavirus-like particle-immunostimulating complex boosting vaccine regimen
Clin Vaccine Immunol
Cited by (63)
Rotavirus
2023, Molecular Medical Microbiology, Third EditionImpact of maternal and pre-existing antibodies on immunogenicity of inactivated rotavirus vaccines
2022, VaccineCitation Excerpt :Nevertheless, maternal and pre-existing antibodies in newborns and infants inhibit the immunogenicity of multiple vaccines including that of live attenuated rotavirus vaccines [16,25–30]. Live attenuated rotavirus vaccines show effectiveness in developed countries, such as Europe and the US, but have shown decreased protective efficacy in low- and middle-income countries (LMIC) [7,16]. This phenomenon may be related to the activity of maternal antibodies, seasonal rotavirus epidemics, co-administration of rotavirus vaccines with oral polio vaccine (OPV), intestinal microbial composition [31] and enteric pathogens, malnutrition, environmentally-caused bowel diseases, frequent reinfection in a locale with high viral diversity [32], HIV, and histo-blood group antigen types [8,9].
- ☆
Clinical trials registration: NCT00439660 and ISRCTN57452882.